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Terminación hipersensible de la respuesta hipóxica por un interruptor de proteínas desordenado
Rebecca B Berlow1, H Jane Dyson1, Peter E Wright1
1Department of Integrative Structural and Computational Biology and Skaggs Institute of Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Nature
|March 9, 2017
Resumen
La proteína CITED2 reduce rápidamente la respuesta hipóxica celular mediante el desplazamiento de HIF-1α de TAZ1. Esto ocurre a través de un complejo transitorio, promoviendo la liberación de HIF-1α y activando un circuito de retroalimentación negativa sensible.
Área de la Ciencia:
- Biología molecular
- Señalización celular
- Interacciones proteína-proteína
Sus antecedentes:
- La respuesta celular a la hipoxia es crucial para la supervivencia y la adaptación.
- El factor inducible a la hipoxia 1 alfa (HIF-1α) regula los genes adaptativos a través del dominio TAZ1 de la CBP/p300.
- CITED2 actúa como un regulador de retroalimentación negativa al competir por la unión TAZ1.
Objetivo del estudio:
- Para aclarar el mecanismo molecular por el cual CITED2 desplaza HIF-1α de TAZ1.
- Comprender cómo CITED2 activa el circuito de retroalimentación negativa que controla la respuesta hipóxica.
Principales métodos:
- Se investigó la interacción entre CITED2, HIF-1α y TAZ1.
- Caracterizó el papel del motivo LP ((Q / E) L conservado en la unión y el desplazamiento de TAZ1.
- Utilizó estudios sobre proteínas intrínsecamente desordenadas para explicar el interruptor regulatorio.
Principales resultados:
- El CITED2 humano desplaza el HIF-1α formando un complejo ternario transitorio con el TAZ1.
- El motivo LPEL de CITED2 compite por el mismo sitio de unión, induciendo un cambio conformacional en TAZ1.
- Este cambio de conformación aumenta alostericamente la disociación de HIF-1α, activando un rápido circuito de retroalimentación negativa.
Conclusiones:
- CITED2 activa un circuito de retroalimentación negativa muy sensible para atenuar la respuesta hipóxica.
- La regulación de la hipersensibilidad se basa en las propiedades únicas de las proteínas intrínsecamente desordenadas.
- Este mecanismo probablemente representa una estrategia celular común para una respuesta rápida a las señales ambientales.
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